Anaphylaxis is a serious, acute allergic reaction that often requires emergency room treatment. Pumphrey R. S. H., “Lessons for Management of Anaphylaxis from a Study of Fatal Reactions,” Clin. Exp. Allergy, 30:1144-50 (2000). It contributes to, or complicates, the course of one out of every 2,700 hospitalized patients (Kemp S. F., et al., “Anaphylaxis. A Review of 266 Cases,” Arch. Intern. Med., 155:1749-54 (1995)) and, if not treated properly and promptly, can result in death. Because the number of allergic reactions in the United States and in many European countries is progressively increasing, the incidence of anaphylaxis is also expected to increase. Neugut A. I., et al., “Anaphylaxis in the United States: an Investigation into its Epidemiology,” Arch. Intern. Med., 161:15-21 (2001).
Epinephrine, also known as adrenaline, is the drug of choice for the initial treatment of anaphylaxis. See AAAAI Directors, “Position Statement: The Use of Epinephrine in the Treatment of Anaphylaxis,” J. Allergy Clin. Immunol., 94(4):666-68 (1994). Indeed, the FDA has recognized epinephrine “as not only safe and effective, but essential for the treatment of anaphylaxis.” NDA 19-430, 1985, Nicklas, Medical Officer Review. Failure to administer epinephrine promptly is considered a most important fact contributing to death of patients with anaphylaxis. Yunginger J. W., et al., “Fatal Food-Induced Anaphylaxis,” J. Am. Med. Assoc., 260:1450-52 (1988); Sampson H. A., et al., “Fatal and Near-fatal Anaphylactic Reactions to Food in Children and Adolescents,” New Engl. J. Med., 327:380-84 (1992).
Despite the beneficial role of epinephrine in treating anaphylaxis, significant problems with current administration methods greatly compromise treatment. Goldberg, et al., “Insect Sting-Inflicted Systemic Reactions: Attitudes of Patients with Insect Venom Allergy Regarding After-Sting Behavior and Proper Administration of Epinephrine,” J. Allergy Clin. Immunol., 106:1184-89 (2000). Numerous studies have emphasized problems with existing treatment options. See e.g., Korenblat P., et al., “A Retrospective Study of Epinephrine Administration for Anaphylaxis: How Many Doses are Needed?” Allergy Asthma Proc., 20:383-86 (1999); Goldberg, et al. Because epinephrine is not orally active, it currently must be given by injection, with substantial variability existing in the plasma concentrations achieved within and between dosing modalities. For example, both the rate of absorption and the peak concentration of epinephrine vary widely with intramuscular (IM) injections with the coefficient of variance (CV) often approaching 50%. Simons F. E. R., et al., “Epinephrine Absorption in Children with a History of Anaphylaxis,” J. Allergy Clin. Immunol., 101:33-37 (1998); Gu X., et al., “Epinephrine Absorption after Different Routes of Administration in an Animal Model,” Biopharm. Drug Dispos., 20:401-5 (1999); Simons F. E., et al., “Epinephrine Absorption in Adults: Intramuscular versus Subcutaneous Injection,” J. Allergy Clin. Immunol., 108:871-73 (2001). With subcutaneous (SC) injections, the time to peak concentration is delayed relative to the IM route, and even greater variability is observed in both the peak concentration achieved and the time to achieve peak concentration. Simons, et al., (1998); Gu, et al. These delays in treatment and lack of predictability significantly compromise patients.
Epinephrine has been used safely with a pulmonary delivery method for years as an over-the-counter (OTC) product for the temporary relief of shortness of breath, tightness of chest and wheezing due to bronchial asthma. PRIMATENE® Mist, Physicians' Desk Reference (2000). A pulmonary form of epinephrine, no longer marketed, was a preferred treatment for anaphylaxis in certain European countries. Medihaler-Epi, Compendium of Data Sheets and Summaries of Product Characteristics, APBI, 693-94 (1998); Muller, et al., “Withdrawal of the MEDIHALER®-epi/ADRENALINE MEDIHALER®,” Allergy, 53:619-20 (1998).
The EPIPEN® Auto-Injector is an example of a product currently approved in the United States for the self-administration of epinephrine for allergic emergencies. It is intended to provide sufficient arrest of an anaphylactic reaction to allow the patient sufficient time to seek further appropriate medical care. EPIPEN®, Physicians' Desk Reference, 56th ed. Montvale, N.J., Medical Economic Company, Inc., 1236 (2002). Although the EPIPEN® Auto-Injector is recognized as beneficial, it nonetheless has limitations widely acknowledged by the medical community. First, there exists a significant reluctance among patients to self-inject. Thus, they often wait long periods of time prior to administering the EPIPEN® or refrain from treating themselves altogether. Goldberg, et al. These delays greatly compromise their safety, for anaphylactic symptoms generally reach their peak within 30 minutes. Atkinson, et al., “Anaphylaxis,” Med. Clin. North Am., 76(4):841-55 (1992); Kemp, et al.; Korenblat, et al. Additionally, for the patients who die, time to death is on the order of 15 minutes following venom and 30 minutes following food exposure. See Pumphrey. Consequently, authorities stress the importance of rapid epinephrine intervention to reduce morbidity and mortality. Secondly, the wide variability in plasma concentrations generally achieved following injection is exacerbated by the patient's poor injection procedures, resulting from self-injection at unexpected and infrequent times, under panic-provoking circumstances. Goldberg, et al. Reliability problems associated with self-administration of epinephrine increase the danger of patients receiving inadequate treatment within the required time frame. R. A. Sabroe, et al., “An Audit of the Use of Self-Administered Adrenaline Syringes in Patients with Angio-Oedema,” British J. of Dermatology, 146 (4):615-20 (2002). Thirdly, one survey reported that approximately 35% of patients required re-injection with a second EPIPEN®, with 20% of those patients exhibiting even the most mild reaction requiring at least two injections. Korenblat, et al. Thus, depending on the severity of a patient's symptoms, multiple EPIPEN® injections may be necessary.
Therefore, a need exists for more reliable, non-invasive, patient-friendly methods and means for patients to self-administer epinephrine.